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Steady-state plasma concentrations of (R)- (ie, the active form), (S)-, and (R,S)-methadone were measured in 14 addict patients in methadone maintenance treatment, before and after introduction of quetiapine, administered at a mean dosage of 138 mg/d (SD, 87 mg/d; median, 125 mg/d; range, 50-300 mg/d) during a mean period of 30 days (SD, 8 days; median, 30 days; range, 20-48 days). Eleven patients were genotyped as being CYP2D6 extensive metabolizers (EMs) and 3 patients as poor metabolizers. Eleven patients had the ABCB1 3435 CT or CC genotypes, and 3 patients had the ABCB1 3435TT genotype, the latter genotype being associated with lower P-glycoprotein activity. Quetiapine significantly increases (R)-methadone concentration-dose ratios in the whole group [increase for (R)-methadone: mean, +21%; SD, +28%; median, +13%; range, −23% to +85%; P = 0.026], but not for (S)-methadone (mean, +23%; SD, +43%; median, +6%; range, −30% to +115%; P = 0.12) or for (R,S)-methadone (mean, +21%; SD, +34%; median, +9%; range, −21% to +95%; P = 0.064). The mean increases of (R)-methadone concentration-dose ratios were of 7%, 21%, and 30% in the CYP2D6 poor metabolizers, heterozygous EMs, and homozygous EMs, respectively, whereas they were of 3%, 23%, and 33% in the subjects with the ABCB1 3435TT, CT, and CC genotypes, respectively. Thus, quetiapine increases the plasma concentrations of (R)-methadone, possibly in part by an interaction with CYP2D6 and/or with the P-glycoprotein transporter system. No signs of overmedication caused by increased methadone plasma concentrations were noticed by the staff or reported by the patients.